Human mixed lymphocyte culture (MLC) can be used to generate natural killer (NK) or NK-like cytotoxicity. This cytotoxicity is not directed against alloantigens and can be generated from NK-inactive precursor cells. This research involves a detailed study of this phenomenon in order to determine the relationship of T-cell function to NK cytotoxicity. The experimental goals of the research include studies on the specificity of MLC-induced NK cytotoxicity by an analysis of reactivity against a large panel of target cells. Special emphasis will be given to reactivity against autochthonous biopsy obtained tumor cells. The phenotype of MLC-induced NK cells will be studied in order to determine the relationship of these cells to human T cells. The nature of the precursor cells required to generate this response will be examined both from the peripheral blood and from other lymphoid compartments such as the thymus. Preliminary data indicate that cytotoxic cells with NK activity can be generated from human thymocytes by allostimulation if IL-2 is present. This is an excellent model for studying the relationship of NK cells to T cells. Regulatory cells for the expression and induction of NK cytotoxicity will be further investigated. Our results indicate that cells capable of suppressing NK-effector function can be generated in vitro. These studies are designed to provide a more comprehensive understanding of the cell types involved in the generation of NK cytotoxicity, their relationship to T-cell functions, and their possible significance in human cancer. (LB)